Discovery of Prostamide F2α and Its Role in Inflammatory Pain and Dorsal Horn Nociceptive Neuron Hyperexcitability

Authors

Luisa Gatta, Second University of Naples
Fabiana Piscitelli, Institute of Biomolecular Chemistry
Catia Giordano, Second University of Naples
Serana Boccella, Second University of Naples
Aron H. Lichtman, Virginia Commonwealth UniversityFollow
Sebatino Maione, Second University of Naples
Vincenzo Di Marzo, Institute of Biomolecular Chemistry

Document Type

Article

Original Publication Date

2012

Journal/Book/Conference Title

PLOS ONE

Volume

7

DOI of Original Publication

10.1371/journal.pone.0031111

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0031111

Date of Submission

November 2014

Abstract

It was suggested that endocannabinoids are metabolized by cyclooxygenase (COX)-2 in the spinal cord of rats with kaolin/λ-carrageenan-induced knee inflammation, and that this mechanism contributes to the analgesic effects of COX-2 inhibitors in this experimental model. We report the development of a specific method for the identification of endocannabinoid COX-2 metabolites, its application to measure the levels of these compounds in tissues, and the finding of prostamide F2α (PMF2α) in mice with knee inflammation. Whereas the levels of spinal endocannabinoids were not significantly altered by kaolin/λ-carrageenan-induced knee inflammation, those of the COX-2 metabolite of AEA, PMF2α, were strongly elevated. The formation of PMF2α was reduced by indomethacin (a non-selective COX inhibitor), NS-398 (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor). In healthy mice, spinal application of PMF2α increased the firing of nociceptive (NS) neurons, and correspondingly reduced the threshold of paw withdrawal latency (PWL). These effects were attenuated by the PMF2α receptor antagonist AGN211336, but not by the FP receptor antagonist AL8810. Also prostaglandin F2α increased NS neuron firing and reduced the threshold of PWL in healthy mice, and these effects were antagonized by AL8810, and not by AGN211336. In mice with kaolin/λ-carrageenan-induced knee inflammation, AGN211336, but not AL8810, reduced the inflammation-induced NS neuron firing and reduction of PWL. These findings suggest that inflammation-induced, and prostanoid-mediated, enhancement of dorsal horn NS neuron firing stimulates the production of spinal PMF2α, which in turn contributes to further NS neuron firing and pain transmission by activating specific receptors.

Rights

Copyright: © 2012 Gatta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Pharmacology and Toxicology Publications